PROJECT 1. HUMAN STUDIES OF ANESTHETIC ACTION General anesthesia is a fascinating man-made, neurophysiological phenomenon that has been developed empirically over many years to enable safe and humane performance of surgical and non-surgical procedures. Specifically it is a drug-induced condition consisting of unconsciousness, amnesia, analgesia and immobility, along with physiological stability. General anesthesia is administered daily to 60,000 patients in the United States, the mechanisms for how anesthetics act in the brain to create the states of anesthesia are not well understood. Significant progress has been made recently in characterizing the molecular sites that anesthetics target. However, how actions at specific molecular targets lead to the behavioral states is less well understood. Addressing this issue requires a systems neuroscience approach to define how actions of the drugs at specific molecular targets and neural circuits lead to a behavioral state of general anesthesia. In this program project entitled, Integrated Systems Neuroscience Studies of Anesthesia, we will develop an integrated systems neuroscience program consisting of human, non-human primate, rodent and modeling studies of four anesthetics: the GABAA agents, propofol and sevoflurane; the alpha-2 adrenergic agonist, dexmedetomidine; and the NMDA receptor antagonist, ketamine. The program project will also include a DATA ANALYSIS CORE, which will provide assistant with data analysis and conduct research on statistical methods. The Specific Aims are to understand how the actions of the anesthetics at specific molecular targets and neural circuits produce the oscillatory dynamics (EEG rhythms, changes in LFPs and neural spiking activity) that are likely a primary common mechanism through which anesthetics create altered states of arousal (sedation, hallucination, unconsciousness). In our first set of human studies we will empanel a cohort of normal human volunteers. Each volunteer will receive a controlled-dosing of one of the anesthetics while executing a behavioral task. The controlled-dosing of the anesthetic will be systematically increased to induce loss of consciousness then systematically decreased to allow recovery. During induction, maintenance and recovery, we will record in addition to standard physiological variables, up to 256-leads of EEG activity. We will characterize the altered states of arousal induced by each anesthetics by relating the dynamics of the neurophysiological and physiological variables to the changes in behavioral. In our second set of human studies we will study specifically sevoflurane and ketamine induced sedation and unconsciousness in neurosurgical patients with implanted intracortical electrodes. These latter studies provide the unique opportunity to record and study multiple single neuron spiking activity and local field potentials in the human brain during loss and recovery of consciousness. These studies will also provide fundamental new knowledge about the neurophysiology of the brain's arousal circuits that will be relevant to problems such as coma, sleep disorders, pain and depression.